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Sci Transl Med. 2016 Dec 21;8(370):370ra180. doi: 10.1126/scitranslmed.aag2942.

Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM.

Author information

1
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
2
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
3
Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-744, South Korea.
4
Department of Cancer Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
5
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. mlim3@jhmi.edu.

Abstract

The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immune response. We show that LC combined with anti-programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8+ cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo- and immunotherapy had differential effects on anti-PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti-PD-1. The results of this work could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types.

PMID:
28003545
PMCID:
PMC5724383
DOI:
10.1126/scitranslmed.aag2942
[Indexed for MEDLINE]
Free PMC Article

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